Process for preparing growth hormone secretagogues

ABSTRACT

This invention relates to improved processes for preparing compounds of Formula II,and compounds of Formula III,wherein R&lt;1&gt;, R&lt;2&gt;, R&lt;3 &gt;and Prt are defined as set forth in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 09/496,075, filed Feb.1, 2000, now U.S. Pat. No. 6,541,634 B1 which claims the benefit of U.S.Provisional Application No. 60/122,745, filed Feb. 26, 1999.

BACKGROUND OF THE INVENTION

This invention relates to an improved process for preparing compounds ofFormula II comprising coupling a compound of Formula IV with a compoundof Formula V. This invention also relates to an improved process forpreparing compounds of Formula III by coupling a compound of Formula IVwith a compound of Formula V and subsequent deprotection of theresulting Prt-protected compound of Formula II.

Commonly assigned International Patent Application Publication No.WO97/24369, hereinafter referred to as the '369 application, which isincorporated herein by reference, discloses certain growth hormonesecretagogue compounds of Formula I,

wherein the definitions of the variables are disclosed therein. Saidcompounds are disclosed in the '369 application to have utility intreating, inter alia, osteoporosis.

Compounds of Formula II,

are disclosed in the '369 application as intermediates in a process toprepare the compounds of Formula III,

which are within the scope of the disclosure of said internationalapplication.

The process disclosed in the '369 application requires coupling acompound of Formula IV with a compound of Formula V. The first step inthe coupling reaction is the reaction of a compound of Formula IV belowwith an organic amine to form the free base of the compound of FormulaIV and the organic amine salt of tartaric acid. The next step in thedisclosed process is a filtration step to remove the organic amine saltof tartaric acid. This was thought to be necessary to eliminate thepossibility of reaction of tartaric acid with the compound of Formula IVunder the coupling conditions. Due to the racemization of the 3aposition of the pyrazolo[4,3-c]pyridine which occurs at roomtemperature, this filtration had to be performed cryogenically, i.e., atreduced temperatures. When operating the coupling reaction on a bulkscale, cryogenic filtration presents technical problems, e.g.,entrainment, slow filtration, a need to use additional equipment andextra handling. This results in reduced yields of product. In theprocess of this invention, the cryogenic filtration is avoided,resulting in a more streamlined process and an improved chemical andoptical yield.

SUMMARY OF THE INVENTION

This invention is directed to a process, designated Process A, ofpreparing a compound of Formula II,

wherein:

R¹ is —(C₁-C₁₀)alkyl optionally substituted with up to three fluoroatoms;

R² is phenylmethyl or 2-pyridylmethyl;

R³ is —(C₁-C₅)alkyl-O—(C₀-C₅)alkylphenyl, where the phenyl substituentin the definition of R³ is optionally substituted with up to threefluoro atoms; and

Prt is an amine protecting group,

comprising:

a) mixing an appropriate chiral tartrate salt having the structure ofFormula IV,

wherein R¹ and R² are as defined above,

and an organic amine in a reaction inert solvent at a temperature ofabout −68° C. to about −40° C. to form a slurry;

b) adding a compound of the Formula V,

wherein R³ and Prt are as defined above, to said slurry to form areaction mixture comprising the tartrate salt of the organic amine, thefree base of a compound of Formula IV and a compound of the formula V;and

c) adding a coupling reagent to said reaction mixture to form a compoundof Formula II.

A preferred process within Process A, designated Process B, is a processwherein said compound of Formula IV is suspended in said solvent priorto the addition of said organic amine.

A preferred process within Process B, designated Process C, is a processwherein said slurry is warmed to about −50° C. prior to step b.

Another preferred process within Process A, designated Process D, is theprocess wherein: in step a, said organic amine is triethylamine; in stepb, R³ is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl andPrt is t-butyloxycarbonyl; and in step c, said coupling reagent ispropane phosphonic acid anhydride.

A preferred process of Process D, designated Process E, is a processwherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process of Process E is a process wherein the compound ofFormula II selected from(1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester and(1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester is prepared.

Another preferred process of Process E is a process wherein a compoundof Formula IIA,

is prepared.

Another preferred process of Process E is the process wherein a compoundof Formula IIB,

is prepared.

Another preferred process within Process B, designated Process F, is theprocess wherein: in step a, said organic amine is triethylamine; in stepb, R³ is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl andPrt is t-butyloxycarbonyl; and in step c, said coupling reagent ispropane phosphonic acid anhydride.

A preferred process within Process F, designated Process G, is a processwherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process within Process F is a process wherein the compoundof Formula II selected from(1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester and(1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester is prepared.

Another preferred process within Process F is a process wherein acompound of Formula IIA,

is prepared.

Another preferred process within Process F is a process wherein acompound of Formula IIB,

is prepared.

Another preferred process within Process C, designated Process H, is aprocess wherein: in step a, said organic amine is triethylamine; in stepb, R³ is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl andPrt is t-butyloxycarbonyl; and in step c, said coupling reagent ispropane phosphonic acid anhydride.

A preferred process within Process H, designated Process I, wherein R¹is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process within Process I is a process wherein the compoundof Formula II selected from(1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester and(1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester is prepared.

Another preferred process within Process I is a process wherein acompound of Formula IIA,

is prepared.

Another preferred process within Process I is a process wherein acompound of Formula IIB,

is prepared.

This invention is also directed to a process, designated Process J, forpreparing a compound of Formula III,

wherein:

R¹ is —(C₁-C₁₀)alkyl optionally substituted with up to three fluoroatoms;

R² is phenylmethyl or 2-pyridylmethyl; and

R³ is —(C₁-C₅)alkyl-O—(C₀-C₅)alkylphenyl, where the phenyl substituentin the definition of R³ is optionally substituted with up to threefluoro atoms, comprising:

a) mixing an appropriate chiral tartrate salt of the Formula IV,

wherein R¹ and R² are as defined above, and an organic amine in areaction inert solvent at a temperature of about −68° C. to about −45°C. to form a slurry;

b) adding a compound of the Formula V,

wherein R³ and Prt are as defined above, to said slurry to form areaction mixture comprising the tartrate salt of the organic amine, thefree base of a compound of Formula IV and a compound of the Formula V;

c) adding a coupling reagent to said reaction mixture to form a compoundof Formula II; and

d) reacting said compound of Formula II with a suitable deprotectingreagent to form a compound of Formula III.

A preferred process within Process J, designated Process K, is a processwherein said compound of Formula IV is suspended in said solvent priorto the addition of said organic amine and the additional step of warmingsaid slurry to about −50° C. to about −40° C. is effected prior to stepb.

A preferred process within Process K, designated Process L, is a processwherein said Prt is Boc and said Boc is removed by reacting saidcompound of Formula II with an acid.

A preferred process within Process L, designated Process M, is a processwherein said acid is methanesulfonic acid.

A preferred process within Process M, designated Process N, is a processwherein: R³ is phenylmethyloxymethyl or2,4-difluorophenylmethyloxymethyl; in step b, said organic amine istriethylamine; and in step c), said coupling reagent is propanephosphonic acid anhydride.

A preferred process within Process N, designated Process O, is a processwherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process within Process O is a process wherein said compoundof Formula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamideis prepared.

Another preferred process within Process O is a process wherein acompound of formula IIIA,

is prepared.

Another preferred process within Process O is a process wherein acompound of formula IIIB,

is prepared.

Another preferred process within Process L, designated Process P, is aprocess wherein said acid is trifluoroacetic acid.

A preferred process within Process P, designated Process R, is a processwherein: R³ is phenylmethyloxymethyl or2,4-difluorophenylmethyloxymethyl; in step b, said organic amine istriethylamine; and in step c, said coupling reagent is propanephosphonic acid anhydride.

A preferred process within Process R, designated Process S, is a processwherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process within Process S is a process wherein said compoundof Formula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamideis prepared.

Another preferred process within Process S is a process wherein acompound of formula IIIA,

is prepared.

Another preferred process within Process S is a process wherein acompound of formula IIIB,

is prepared.

Another preferred process within claim K, designated Process T, is aprocess wherein said Prt is Boc and said Boc is removed by reacting saidcompound of Formula II with an acid.

A preferred process within Process T, designated Process U, is a processwherein said acid is methanesulfonic acid.

A preferred process within Process U, designated Process V, is a processwherein: R³ is phenylmethyloxymethyl or2,4-difluorophenylmethyloxymethyl; in step b, said organic amine istriethylamine; and in step c, said coupling reagent is propanephosphonic acid anhydride.

A preferred process within Process V, designated Process W, is a processwherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process within Process W is a process wherein said compoundof Formula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamideis prepared.

Another preferred process within Process W is a process wherein acompound of formula IIIA,

is prepared.

Another preferred process within Process W is a process wherein acompound of formula IIIB,

is prepared.

Another preferred process within Process T, designated Process X, is aprocess wherein said acid is trifluoroacetic acid.

A preferred process within Process X, designated Process Y, is a processwherein: R³ is phenylmethyloxymethyl or2,4-difluorophenylmethyloxymethyl; in step b), said organic amine istriethylamine; and in step c, said coupling reagent is propanephosphonic acid anhydride.

A preferred process within Process Y, designated Process Z, is a processwherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.

A preferred process within Process Z is a process wherein said compoundof Formula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamideis prepared.

Another preferred process within Process Z is a process wherein acompound of formula IIIA,

is prepared.

Another preferred process within Process Z is a process wherein acompound of formula IIIB,

is prepared.

This invention is also directed to a process for preparing a compound offormula XX,

comprising the following consecutive steps:

a) reacting said 4-oxo-piperidinecarboxylic acid methyl ester,hydrochloride with di-t-butyl-dicarbonate and triethylamine in isopropylether to form 4-oxo-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl)3-methyl ester;

b) reacting said 4-oxo-1,3-piperidinedicarboxylic acid1-(1-dimethylethyl) 3-methyl ester with benzyl bromide and potassiumcarbonate in tetrahydrofuran to form4-oxo-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl)3-methyl ester;

c) reacting said 4-oxo-(phenylmethyl)-1,3-piperidinedicarboxylic acid1-(1-dimethylethyl) 3-methyl ester with methylhydrazine in acetic acidand methyl-t-butyl ether to form2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylicacid 1,1-dimethylethyl ester; and

d) reacting said2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylicacid 1,1-dimethylethyl ester with trifluoroacetic acid to form(3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one;

e) reacting said(3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-onewith L-tartaric acid in acetone and water to form said L-tartrate saltof formula XX.

This invention is particularly directed to a process as set forth in theimmediately preceding paragraph wherein said L-tartaric acid is addedwithout isolating said(3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one.In particular, the compound of formula XX is isolated as a dihydrate.The desired crystal form is isolated upon cooling from an appropriatemixture of solvents.

This invention is also directed to a polymorph of a dihydrate of acompound of formula XX:

This invention is particularly directed to the polymorph having theatomic coordinates and equivalent isotropic displacement coefficients asset forth in Table 1. This invention is also particularly directed tothe polymorph having the X-Ray crystal structure according to FIG. 1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-Ray crystal structure of the compound of formula XX,collected on a Siemens R3RA/v diffractometer. The crystal structureshows that the compound is a dihydrate of the L-tartrate salt of saidcompound.

DETAILED DESCRIPTION OF THE INVENTION

The following schemes illustrate the synthesis of the compounds ofFormulas II and III. The symbol “*” indicates a stereochemical center.In the scheme “Prt” is used to indicate any suitable amine protectinggroup known to those skilled in the art. In the description followingeach scheme, the amine protecting group Prt is illustrated with thepreferred amine protecting group BOC, though it will be recognized thatother amine protecting groups may also be utilized.

Compounds of Formula IV wherein Alk is methyl or ethyl, R¹, R² and Prtare as defined above, e.g., the compounds of formula 1e, are prepared asset forth in Scheme 1 or 1a. According to Scheme 1, step a, a compoundof formula la is mixed with a reaction inert polar aprotic solvent suchas acetone, methyl ethyl ketone, DMF (dimethylformamide) or preferablytetrahydrofuran at about 0° C. to room temperature, preferably roomtemperature. To the solution is added R²—X, wherein X is a leaving groupsuch as halo or an alkyl- or aryl-sulfonate; a base such as potassiumt-butoxide or a carbonate such as Li₂CO₃, Cs₂CO₃ or preferably potassiumcarbonate; and optionally a phase transfer reagent such as potassiumiodide or tetrabutylammonium iodide. In the case where postassiumcarbonate is used as base, it is preferred that a phase transfer reagentis not used. It is preferred that, where R² is benzyl, R²—X is benzylbromide and that where R² is 2-pyridylmethyl, R²—X is picolyl chloridehydrochloride. After stirring at about −20° C. to about 70° C. for about2 to 16 hours, preferably at 60° C. to about 65° C. for about 12 hours,the product is isolated from the reaction mixture according totechniques well known to those skilled in the art. This step ispreferably carried out as set forth in Preparation Five, Step D, below.

According to step b, a hydrazine derivative is reacted with a compoundof formula 1b. Preferably the hydrazine derivative is a 70% aqueoussolution of CF₃CH₂NHNH₂ (trifluoroethylhydrazine) or anhydrous CH₃NHNH₂(methylhydrazine) which is used as an aqueous solution in ethanol, wateror toluene. When the 70% solution of trifluoroethylhydrazine is used, itis further preferred that the 70% aqueous solution of CF₃CH₂NHNH₂ isextracted with toluene. To a solution of a compound of formula 1b in anorganic solvent such as ethanol, toluene or preferably methylt-butylether (MTBE), is first added the anhydrous 2,2,2-trifluoroethylhydrazine or methyl hydrazine, followed by acetic acid. Preferably, MTBEis used to prevent the reaction mixture from reaching a dangerously hightemperature. The reaction mixture is heated at about 50° C. to about110° C. for about 30 minutes to 24 hours, preferably about 60° C. forabout 12 to about 15 hours. The reaction mixture is cooled to roomtemperature and neutralized with an aqueous base such as NaHCO₃. Whereused herein, the term “room temperature” means a temperature of about20° C.-25° C. The organic layer is separated and worked up usingstandard methods known in the art to yield a compound formula 1c. Thisstep is preferably carried out as set forth in Preparation Five, Step E,below.

According to step c, an acid such as HCl in IPE or ethanol,trifluoroacetic acid (TFA) or an alkyl sulfonic acid such asmethanesulfonic acid is added to a solution of a compound of formula 1cin a reaction inert organic solvent such as EtOH, IPE or preferablyCH₂Cl₂. The mixture is stirred for about 1 to 12 hours, then cooled toabout 0° C. to about room temperature, preferably to room temperature.After the reaction is complete, a base such as triethylamine or NH₄OH isadded to the mixture. The mixture is allowed to warm to roomtemperature, is diluted with additional organic solvent and worked upusing standard methods known in the art to yield a compound of formula1d. Alternatively and preferably, the compound of formula 1d may be usedwithout isolation in the next step. Step c of Scheme 1 is preferablycarried out in combination with step d of Scheme 1 as set forth inPreparation Five, Step F, below.

According to step d, (D)- or (L)-tartaric acid, preferably (L)-tartaricacid, is added to a compound of formula 1d in acetone/water (about 8:1to about 9:1) at about room temperature. The mixture is stirred at aboutroom temperature to about the reflux temperature of the solvent mixturefor about 1 hour to overnight, e.g., 18 hours, preferably 15 to 18hours. Preferably the compound of formula 1e is isolated as a dihydratecrystal form. Then the solid is filtered, collected and washed with coldacetone, to yield a compound of formula 1e, which is preferably the(L)-tartrate of a single enantiomer. This step is preferably carried outas set forth in Preparation Five, Step F, without isolation of theprecursor free base compound.

Compounds of formula V wherein R³ is difluorobenzyloxymethyl, R²⁵ isalkyl, aryl or substituted aryl and Prt is an amine protecting group,e.g., the compounds of formula 2d, are prepared as set forth in Scheme2. According to step e, to a solution of N-BOC-serine, preferablyN-BOC-(D)-serine, the compound of formula 2a, in THF/DMF (about 1:1 toabout 2:1) at about 0° C. is added n-BuLi or a potassium tert-butoxidesolution. The reaction mixture is stirred at about 0° C. for about 10 toabout 30 minutes, preferably for 20 minutes, then 2,4-difluorobenzylbromide is added. After warming to room temperature and stirring forabout 6 to about 24 hours, the reaction mixture is concentrated in vacuoto remove the THF and an aqueous acid such as 1 N HCl is added to adjustthe mixture to pH of about 3. The reaction mixture is then partitionedbetween water and an organic solvent such as methylene chloride (CH₂Cl₂)or IPE. The organic solution is worked up using standard methods knownin the art to yield the compound of formula 2b, preferably having theR-configuration at the stereocenter, also known as the (D)-enantiomer.

According to step f, to a solution of the compound of formula 2b in anorganic solvent such as THF, CH₂Cl₂, IPE or a mixture thereof,preferably CH₂Cl₂/IPE (about 1:1), is added an alkyl or aryl sulfonicacid such as methanesulfonic acid. The solid is filtered and washed witha CH₂Cl₂/IPE mixture (1:1) to afford the compound of formula 2c,preferably having the R-configuration at the stereocenter, also known asthe (D)-enantiomer.

According to step g, to a solution of the compound of formula 2c inTHF/water (about 4:1) is added2-tert-butoxycarbonylamino-2-methyl-propionicacid-2,5-dioxo-pyrrolidin-1-yl ester and an alkyl amine such astriethylamine. The reaction mixture is stirred at room temperature forabout 1-24 hours and quenched with an aqueous acid such as 10% aqueouscitric acid solution. The mixture is partitioned with an organic solventsuch as ethyl acetate and the organic layer is separated and worked-upusing standard methods known in the art to yield a compound of formula2d, preferably having the R-configuration at the stereocenter also knownas the (D)-enantiomer.

The compound of Formula V wherein R³ is benzyloxymethyl and Prt is Bocis prepared as set forth in Preparation Three, Steps A and B, below.Compounds wherein Prt is an amine protecting group other than Boc areprepared by substituting the appropriate N-protected α-methylalaninederivative for N-t-butyloxycarbonyl-α-methylalanine. AppropriateN-protected α-methylalanine derivatives, if not readily available fromvendors, can be readily prepared from α-methylalanine according tomethods well known to those skilled in the art.

Compounds of formulas II, III and 3c wherein R¹, R² and R³ are asdefined above are prepared according to Scheme 3. According to step h, acompound of formula IV (1e), preferably the (L)-tartrate salt of asingle enantiomer, is slurried at about −68° C. to about −45° C.,preferably at about −68° C. to about −60° C. and most preferably atabout −68° C. with a reaction inert solvent, preferably ethyl acetate.An organic amine, such as diisopropylethylamine, trimethylamine ortriethylamine, preferably triethylamine, is added. During the additionof the organic amine, the temperature is maintained at about −68° C. toabout −45° C. and preferably at about −68° C. to about −60° C. Thereaction mixture is stirred for about 30 to about 120 minutes at atemperature between about −78° C. and about −45° C. The resulting slurrycontains a mixture of the free base of a compound of Formula IV and anorganic amine salt of tartaric acid. To this slurry is added an organicamine such as diisopropylethylamine, trimethylamine or triethylamine,preferably triethylamine. During this addition, the internal temperatureof the reaction mixture is maintained below −50° C. To this reactionmixture, which still contains an organic amine salt of tartaric acid, isadded a compound of Formula V, all at once, while maintaining thetemperature of the reaction mixture at about −68° C. to about −45° C.Then a coupling reagent such as propane phosphonic acid anhydride isadded over a period of about 5 minutes to about 30 minutes. Thetemperature is allowed to warm gradually to about −25° C. to about 0°C., preferably to about −20° C. over the next hour. The reaction mixtureis worked up using standard methods known in the art to yield a compoundof Formula II, preferably having the absolute and relative 3a(R), 1(R)configuration.

According to step i, an acid such as HCl in EtOH, or methanesulfonicacid or trifluoroacetic acid in CH₂Cl₂ is added at about 0° C. to roomtemperature to a compound of Formula II in a reaction inert solvent suchas CH₂Cl₂, IPE or THF. The mixture is stirred for about 40 minutes toabout 4 hours at room temperature, then a saturated aqueous base such asNa₂CO₃ or NaHCO₃ is added until the solution is at neutral (7.0) pH. Theorganic layer is separated and worked up using standard methods known inthe art to yield a compound of Formula II, preferably having theabsolute and relative 3a(R), 1(R) configuration.

According to step j, to a solution of a compound of Formula III in analcohol such as methanol, ethanol or isopropanol, preferablyisopropanol, is added L-(+) tartaric acid. When methanol or ethanol isused, the reaction mixture is stirred for about 1 hour to about 12 hoursand is then filtered and the filtrate is concentrated. In either case,the crude residue is diluted with an organic solvent such as ethylacetate, heated and slowly allowed to cool to room temperature. Thesolid is filtered and dried to give the L-(+) tartaric acid salt of thecompound of formula 3c, preferably having the absolute and relative3a(R), 1(R) configuration.

The starting materials and reagents used in the processes of thisinvention can be purchased from common vendors or prepared according tomethods well known to those skilled in the art of organic chemistry. Inparticular, 4-oxo-(phenylmethyl)-3-piperidinecarboxylic acid methylester, hydrochloride may be prepared as set forth in Preparation Five,Step A below or, alternatively, may be prepared as set forth in Hoffman,N. and Erinjeri, A., J. Heterocyclic Chem., 1965, 2, 326.

Where used herein, the term “reaction inert solvent” means a solventwhich does not interact with starting materials, reagents, intermediatesor products in a manner which adversely affects the yield of the desiredproduct. Said reaction inert solvent in step a is a solvent in which thefree base of the compound of Formula IV is soluble.

Where used herein, the term “organic amine” means a lower alkyl amine,such as triethylamine, trimethylamine or diisopropylethylamine; or acyclic amine, such as piperidine, pyrrolidine or N-methylmorpholine.

The following examples are provided for the purpose of furtherillustration only and are not intended to be a limitation on thedisclosed invention.

Silica gel was used for column chromatography. Melting points were takenon a Buchi 510 apparatus and are uncorrected. Proton NMR spectra wererecorded on a Varian XL-300, Bruker AC-300, Varian Unity 400 or BrukerAC-250 at 25° C. Those skilled in the art of organic chemistry willrecognize that the NMR data obtained herein can also be obtained onother NMR insturments which are obtainable from a variety of vendorswell known to those skilled in the art. Chemical shifts are expressed inparts per million down field from trimethylsilane.

General Procedure A: (Cleavage of a Boc-protecting group from aBoc-protected amine using concentrated HCl): The Boc-protected amine isdissolved in a minimum volume of ethanol and the resulting solution iscooled to about 0° C. and concentrated HCl (typically about 1 to 4 mLper mmol of Boc-protected amine) is added and the reaction mixture iswarmed to room temperature and stirred for about one hour to about 2.5hours (or the time required for complete disappearance of the startingmaterial to a more polar product as judged by thin layerchromatography). The resulting solution or suspension is concentratedand the residue is coevaporated several times with added ethanol toafford the free amine which is used without further purification orpurified as specified.

EXAMPLE 1(1-(2-(3a(R)-Benzyl-2-methyl-3-oxo-2.3,3a.4,6.7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

To a dry, nitrogen purged 1 liter, 4 neck, round bottom flask, equippedwith a mechanical stirrer, a nitrogen capped condenser, a thermocouple,and an addition funnel was added3a-benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(L)-tartrate (prepared according to Preparation One, Step D, 66.09 g,0.168 moles, 1.12 equivalents) and ethyl acetate (660 mL, 10 volumes). Aslurry formed. The slurry was agitated and cooled to an internaltemperature of −68° C. to −66° C. To the cooled, agitated slurry wasadded triethyl amine (TEA, 58 mL, 42.5 g, 0.42 moles, 2.8 equivalents)via the addition funnel. The internal temperature was maintained at −68°C. to −66° C. during addition. The reaction mixture was agitated forabout 1.5 hours while the internal temperature was warmed to about −52°C. To the reaction mixture (which was a slurry of the tartrate salt oftriethylamine and the free base of3a-benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(L)-tartrate) was added triethylamine (96.5 ml, 70 g, 0.69 moles, 4.6equivalents) over 5 minutes. An internal temperature of −53° C. to −50°C. was maintained during addition. To the reaction mixture was added3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid (prepared according to Preparation Three, Step B, 57.07 g, 0.150moles, 1.0 equivalents), all in one portion. An internal temperature−55° C. to −50° C. was maintained during addition. To the reactionmixture was added propane phosphonic acid anhydride (PPAA, 180 ml, 190g, 2.0 equivalents) as a 50% solution of propane phosphonic acidanhydride in ethyl acetate. The PPAA was added over 15 minutes and theinternal temperature rose to about −30° C. during the addition. Thereaction mixture was agitated at about −30° C. for about 0.5 hours. Thereaction mixture was poured into a vigorously agitated mixture ofdiisopropyl ether (IPE, 660 mL, 10 volumes) and water (660 mL, 10volumes). The resulting biphasic mixture was agitated for 1 hour andthen the reaction mixture was allowed to settle. The aqueous portion wasdecanted and the organic portion was then washed sequentially withaqueous HCl (1N, 165 mL, 2.5 volumes, 1.3 equivalents), 10% aqueousNa₂CO₃ (330 mL, 5 volumes, 2.1 equivalents), and 15% aqueous NaCl (165mL). The washed organic portion was concentrated in vacuo to the loweststirrable volume and to the concentrate was added IPE (300 mL, about 5volumes). The solution was again concentrated in vacuo to the loweststirrable volume. To the concentrate was added IPE (330 mL, about 5volumes) and the solution was heated atmospherically to an internaltemperature of about 67° C. Precipitates were observed and the slurrywas cooled to an internal temperature of about 1° C. over 1 hour withagitation. The solids were filtered and dried in vacuo at about 50° C.to afford 54.85 g of the title compound (60.4% yield).

EXAMPLE TWO2-Amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide(L-Tartrate Salt)

To a 5L, 4 neck, round bottom flask equipped with a mechanical agitator,thermocouple, a condenser and an addition funnel, was addedconsecutively3a(R)-benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(L)-tartrate (prepared according to Preparation One, Step D, 60.57 g,0.10 moles, 1.0 equivalent) and methylene chloride (400 ml, 6.7volumes). The mixture was agitated to afford a clear solution and thesolution was then cooled to an internal temperature of −10° C. to −5° C.To the cooled, agitated solution was added trifluoroacetic acid (TFA,180 ml, 3.0 volumes/23.6 equivalents/2.33 moles) at such a rate that theinternal temperature did not exceed −5° C. The addition was complete inabout 10 minutes. The reaction mixture was then slowly warmed to 8° C.over 1 hour. While maintaining an internal temperature of 10° C.-20° C.,the reaction mixture was brought to pH greater than 8 by slow additionof Na₂CO₃ (1.0 N, 1200 ml, 12 equivalents/12 moles). The reactionmixture was allowed to settle and the organic portion was decanted. Theaqueous fraction was extracted with methylene chloride (2×100 mlportions, 1.65 volumes each). The combined organic fractions were washedwith water (100 mL). The washed organic fraction was concentrated to thelowest stirrable volume by atmospheric distillation and to theconcentrate was added ethyl acetate (2000 ml, 33 volumes). To the ethylacetate solution was added a solution L-tartaric acid (15.05 g, 0.10moles/1 equivalent) in methanol (60 ml, 1 volume). The reaction mixturewas heated and the methanol distilled off. The distillation wascontinued until the internal and head temperature were 77° C.-78° C. andthen the reaction mixture was refluxed for 1-2 hours. The reaction wasthen cooled to about 1 5° C. over several hours. The solids werefiltered, washed with ethyl acetate (200 ml) and dried overnight invacuo at about 50° C. to afford 60.79 g of the title compound (92.7%yield).

EXAMPLE THREE(1-(2-(1(R)-(2,4-Difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicAcid tert-Butyl Ester

To a dry, nitrogen purged 0.5 liter, 4 neck, round bottom flask,equipped with a mechanical stirrer, a nitrogen capped condenser, athermocouple, and an addition funnel were added sequentially3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(L)-tartrate (prepared according to Preparation Two, Step D, 10.35 g,0.0224 moles, 1.12 equivalents) and ethyl acetate (110 mL, 10 volumes).A slurry formed. The slurry was agitated and cooled to an internaltemperature of −68° C. to −60° C. To the cooled, agitated slurry wasadded triethylamine (TEA, 7.75 ml, 5.66 g, 0.056 moles, 2.8 equivalents)via the addition funnel. The internal temperature was maintained at −68°C. to −60° C. during addition. The reaction mixture was agitated forabout 1.5 hours while the internal temperature was warmed to about −62°C. to −52° C. To the reaction mixture (which was a slurry of thetartrate salt of triethylamine and the free base of3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(L)-tartrate) was added triethylamine (12.7 ml, 9.30 g, 0.092 moles, 4.6equivalents) over 5 minutes. An internal temperature of −62° C. to −50°C. was maintained during addition. To the reaction mixture was added2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-3-(2,4-difluoro-benzyloxy)-propionicacid (prepared according to Preparation Four, Step C, 8.34 g, 0.020moles, 1.0 equivalents), all in one portion. An internal temperature of−60° C. to −58° C. was maintained during addition. Propane phosphonicacid anhydride (PPM, 24 mL, 25.5 g, 2.0 equivalents) as a 50% solutionof propane phosphonic acid anhydride in ethyl acetate was diluted withethyl acetate (24 mL, 2.2 volumes) and cooled to about −45° C. The PPMsolution was then added to the reaction mixture. The PPM was added over15 minutes and the internal temperature rose gradually to about −19° C.over about 1 hour. The reaction mixture was poured into a vigorouslyagitated mixture of diisopropyl ether (IPE, 100 mL, 9.1 volumes) andwater (100 mL, 9.1 volumes). The resulting biphasic mixture was agitatedfor 5 minutes and then the reaction mixture was allowed to settle. Theaqueous portion was decanted and the organic portion was then washedsequentially with aqueous HCl (0.5N, 50 mL, 4.5 volumes, 1.3equivalents), saturated aqueous NaHCO₃ (50 mL, 4.5 volumes, ˜2.5equivalents), and 15% aqueous NaCl (50 mL). The washed organic portionwas concentrated in vacuo to afford an oil. The oil was agitated withhexanes (50 mL, about 2.5 volumes) to afford a glassy solid, 13.75 g(96.8% crude yield). The solids were dissolved in chloroform andconcentrated in vacuo to afford an oil. This procedure was repeated withhexanes. Finally, the resultant oil was agitated with hexanes for 16hours. The resultant solids were filtered to afford 10.45 g of the titlecompound (73.6% yield).

EXAMPLE FOUR2-Amino-N-(1(R)-(2.4-difluoro-benzyloxmethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide

(1-(2-(1(R)-(2,4-Difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester (prepared according to Example Three, 17.5 g, 25.3mmol) was deprotected according to the method described in GeneralProcedure A to afford a colorless solid. The product was triturated withdiethyl ether to afford the title compound. (13.6 g, 90%):+Apcl MS(M+H)⁺591.

EXAMPLE FIVE

2-Amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamideL-(+) Tartrate

To a solution of2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide(prepared according to Example Four, 370 g, 0.6 mol) in methanol (4,070mL) in a 12 L round bottom flask equipped with a mechanical stirrer wasadded L-(+) tartaric acid (90 g, 0.6 mol). The reaction mixture wasstirred for about 90 min. at about 22° C., filtered and concentrated.The crude residue was diluted with ethyl acetate (4,560 mL), heated atabout 70° C. and slowly allowed to cool to room temperature over about17 hours. The solid was filtered and dried to give white crystals, mp188-189° C. (348.46 g, yield 76%). ¹H NMR (MeOH, d4) δ: 8.28 (d, 1H),7.59 (t, 1H), 7.41-7.39 (m, 1H), 7.18-7.13 (m, 1H), 6.92 (t, 1H), 5.2(t, 1H), 4.56 (bs, 3H), 4.36 (s, 2H), 4.31-4.25 (m, 1H), 4.13-4.06 (m,1H), 3.78 (d, 2H), 3.21 (t, 1H), 3.18-2.96 (m, 2H), 2.65-2.55 (m, 2H),1.57 (d, 6H). MS: MH+ 611. [a]⁵⁸⁹+22.03 (c=11.9, MeOH).

EXAMPLE SIX

Single Crystal X-Ray Analysis. A representative crystal was surveyed anda 1 Å data set (maximum θ/λ=0.5) was collected on a Siemens R³RA/Vdiffractometer. Atomic scattering factors were taken from theInternational Tables for X-Ray Crystallography.¹ All crystallographiccalculations were facilitated by the SHELXTL² system. All diffractometerdata were collected at room temperature. Pertinent crystal, datacollection, and refinement parameters are summarized in Table I below.

A trial structure was obtained by direct methods. This trial structurerefined routinely. Hydrogen positions were calculated wherever possible.The methyl hydrogens and the hydrogens on the nitrogen and oxygen werelocated by difference Fourier techniques. The hydrogen parameters wereadded to the structure factor calculations but were not refined. Theshifts calculated in the final cycle of least squares refinement wereall less than 0.1 of their corresponding standard deviations. The finalR-index was 4.95%. A final difference Fourier revealed no missing ormisplaced electron density.

The refined structure was plotted using the SHELXTL plotting package(FIG. 1). The absolute configuration was assigned on the knownconfiguration of L-tartaric acid. Coordinates, anisotropic temperaturefactors, distances and angles are available as supplementary material,see Tables II through VI.

TABLE I Single Crystal X-Ray Crystallographic Analysis A. CrystalParameters: formula C₁₄H₁₈N₃O⁺ C₄H₅O₆ ⁻ · 2H₂O (429.4) crystallizationmedium acetone and water (4:1) crystal size, mm 0.05 × 0.12 × 0.32 celldimensions a = 8.235 (3) Å b = 7.032 (2) Å c = 18.106 (6) Å α = 90.0° β= 99.41 (2)° γ = 90.0° V = 1034.4 (6) Å³ space group P2₁ molecules/unitcell 2 density calcd, g/cm³ 1.379 linear absorption factor, mm⁻¹ 0.946B. Refinement Parameters: number of reflections 1174.39 nonzeroreflections (I > 3.0σ) 1025 R-index^(a) 4.95% GOF^(b) 1 secondaryextinction factor^(c), _(χ)52 (8) × 10⁻⁴ a R-index = Σ || Fo | − | Fc|/Σ | Fo | b GOF = [Σw(Fo² − Fc²)²/(m − s)]^(½) where w = [σ² (F) + | g| F²]⁻¹ and g = 0.0005 c F* = F[1 + 0.002_(χ)F²/sin(2θ)]^(−¼)

TABLE II Atomic coordinates (×10⁴) and equivalent isotropic displacementcoefficients (Å² × 10³) x y z U(eq) C(1′) 7050 (7) 12045 (7) 6424 (4)31(1) O(1A′) 5715 (5) 12748 (6) 6097 (3) 41(1) O(1B′) 8234 (5) 12946 (6)6748 (3) 41(1) C(2′) 7120 (6) 9881 (7) 6388 (4) 29(1) O(2′) 8733 (5)9232 (6) 6715 (3) 37(1) C(3′) 6707 (7) 9167 (7) 5599 (4) 32(1) O(3′)7899 (5) 9726 (6) 5160 (3) 47(1) C(4′) 6647 (7) 6999 (7) 5583 (4) 32(1)O(4A′) 5644 (5) 6263 (6) 5971 (3) 39(1) O(4B′) 7465 (5) 6110 (7) 5213(3) 59(1) N(1) 5011 (6) 8379 1995 (3) 43(1) N(2) 4317 (6) 6558 (7) 1896(3) 40(1) C(2A) 2623 (6) 6380 (8) 1541 (4) 55(1) C(3) 5357 (7) 5149 (8)2171 (4) 36(1) O(3) 5039 (5) 3491 (6) 2188 (3) 46(1) C(4) 6998 (6) 6172(8) 2450 (3) 28(1) C(5) 6515 (6) 8177 (8) 2299 (4) 33(1) C(6) 7511 (6)5878 (8) 3290 (4) 39(1) N(7) 8723 (6) 7355 (7) 3591 (3) 40(1) C(8) 8153(7) 9366 (8) 3440 (4) 49(1) C(9) 7643 (7) 9700 (8) 2603 (4) 46(1) C(10)8290 (6) 5440 (8) 1989 (4) 37(1) C(11) 7862 (7) 5776 (8) 11667 (4) 43(1)C(12) 8463 (7) 7317 (8) 853 (4) 69(1) C(13) 8108 (8) 7675 (9) 76 (5)97(1) C(14) 7080 (*) 6405 (9) −336 (5) 96(1) C(15) 6443 (8) 4882 (8) −59(5) 81(1) C(16) 6872 (7) 4533 (8) 705 (4) 75(1) O(1W) 8100 (5) 6278 (7)7609 (3) 54(1) O(2W) 10828 (5) 8138 (7) 5099 (3) 62(1) *Equivalentisotropic U defined as one third of the trace of the orthogonalizedU_(ij) tensor

*Equivalent isotropic U defined as one third of the trace of theorthogonalized U_(ij) tensor

TABLE III Bond Lengths (Å) C(1′)-O(1A′) 1.262(7) C(1′)-O(1B′) 1.229(7)(C1′)-C(2′) 1.525(7) C(2′)-O(2′) 1.4347(6) C(2′)-C(3′) 1.500(9)C(3′)-O(3′) 1.416(8) C(3′)-C(4′) 1.526(7) C(4′)-O(4A′) 1.277(8)C(4′)-O(4B′) 1.201(8) N(1)-N(2) 1.402(5) N(1)-C(5) 1.278(7) N(2)-C(2A)1.443(7) N(2)-C(3) 1.350(7) C(3)-O(3) 1.196(7) C(3)-C(4) 1.541(7)C(4)-C(5) 1.478(7) C(4)-C(6) 1.526(9) C(4)-C(10) 1.544(9) C(5)-C(9)1.465(7) C(6)-N(7) 1.481(7) N(7)-C(8) 1.501(7) C(8)-C(9) 1.524(10)C(10)-C(11) 1.492(9) C(11)-C(12) 1.355(9) C(11)-C(16) 1.380(8)C(12)-C(13) 1.411(12) C(13)-C(14) 1.365(9) C(14)-C(15) 1.327(10)C(15)-C(16) 1.393(11)

TABLE IV Bond Angles (°) O(1A′)-C(1′)-O(1B′) 125.8(5) O(1A′)-C(1′)-C(2′)114.1(5) O(1B′)-C(1′)-C(2′) 120.2(5) C(1′)-C(2′)-O(2′) 109.8(4)C(1′)-C(2′)-C(3′) 111.7(5) O(2′)-C(2′)-C(3′) 109.7(5) C(2′)-C(3′)-O(3′)111.9(4) C(2′)-C(3′)-C(4′) 110.7(5) O(3′)-C(3′)-C(4′) 106.9(5)C(3′)-C(4′)-O(4A′) 114.6(5) C(3′)-C(4′)-O(4B′) 120.7(6)O(4A′)-C(4′)-O(4B′) 124.6(5) N(2)-N(1)-C(5) 107.4(3) N(1)-N(2)-C(2A)118.7(4) N(1)-N(2)-C(3) 113.8(4) C(2A)-N(2)-C(3) 127.5(5) N(2)-C(3)-O(3)126.6(5) N(2)-C(3)-C(4) 104.3(4) O(3)-C(3)-C(4) 129.0(5) C(3)-C(4)-C(5)100.9(4) C(3)-C(4)-C(6) 110.4(5) C(5)-C(4)-C(6) 109.6(5) C(3)-C(4)-C(10)108.2(5) C(5)-C(4)-C(10) 114.0(5) C(6)-C(4)-C(10) 113.0(4)N(1)-C(5)-C(4) 113.4(4) N(1)-C(5)-C(9) 126.2(4) C(4)-C(5)-C(9) 119.5(4)C(4)-C(6)-N(7) 109.4(5) C(6)-N(7)-C(8) 115.0(4) N(7)-C(8)-C(9) 110.7(5)C(5)-C(9)-C(8) 108.4(5) C(4)-C(10)-C(11) 114.5(4) C(10)-C(11)-C(12)120.2(5) C(10)-C(11)-C(16) 121.6(6) C(12)-C(11)-C(16) 118.3(7)C(11)-C(12)-C(13) 122.0(6) C(12)-C(13)-C(14) 115.9(7) C(13)-C(14)-C(15)124.7(8) C(14)-C(15)-C(16) 117.8(6) C(11)-C(16)-C(15) 121.2(6)

TABLE V Anisotropic displacement coefficients (Å² × 10³) U₁₁ U₂₂ U₃₃ U₁₂U₁₃ U₂₃ C(1′) 32 (1) 26 (1) 34(1) 2 (1) 5 (1) −8 (1) O(1A′) 35 (1) 19(1) 67(1) −4 (1) 2 (1) 2 (1) O(1B′) 35 (1) 26 (1) 60(1) −4 (1) −2 (1)−13 (1) C(2′) 32 (1) 17 (1) 36(1) 1 (1) −1 (1) 1 (1) O(2′) 32 (1) 33 (1)43(1) 4 (1) −1 (1) 0 (1) C(3′) 41 (1) 18 (1) 37(1) 6 (1) 6 (1) −6 (1)O(3′) 71 (1) 33 (1) 41(1) −2 (1) 23 (1) 1 (1) C(4′) 28 (1) 27 (1) 39(1)2 (1) 3 (1) 2 (1) O(4A′) 41 (1) 32 (1) 45(1) −7 (1) 10 (1) −9 (1) O(4B′)56 (1) 35 (1) 92(1) 7 (1) 32 (1) −2 (1) N(1) 39 (1) 48 (1) 37(1) 4 (1)−6 (1) 7 (1) N(2) 30 (1) 39 (1) 47(1) 2 (1) −2 (1) −4 (1) C(2A) 27 (1)66 (1) 68(1) −3 (1) −2 (1) −1 (1) C(3) 39 (1) 40 (1) 30(1) 8 (1) 10 (1)−7 (1) O(3) 45 (1) 27 (1) 65(1) −3 (1) 5 (1) 1 (1) C(4) 23 (1) 34 (1)26(1) 0 (1) 2 (1) 3 (1) C(5) 31 (1) 32 (1) 36(1) −1 (1) 6 (1) 0 (1) C(6)38 (1) 38 (1) 38(1) 4 (1) 1 (1) −4 (1) N(7) 39 (1) 42 (1) 34(1) 1 (1) −6(1) −1 (1) C(8) 44 (1) 46 (1) 54(1) −1 (1) 1 (1) −9 (1) C(9) 41 (1) 42(1) 52(1) 6 (1) 2 (1) 0 (1) C(10) 37 (1) 46 (1) 29(1) 6 (1) 9 (1) 4 (1)C(11) 39 (1) 55 (1) 37(1) 10 (1) 7 (1) −2 (1) C(12) 72 (1) 85 (1) 49(1)4 (1) 2 (1) 1 (1) C(13) 103 (1) 108 (1) 82(1) 2 (1) 16 (1) 27 (1) C(14)103 (1) 108 (1) 73(1) 13 (1) 4 (1) 6 (1) C(15) 81 (1) 93 (1) 63(1) −4(1) −6 (1) −17 (1) C(16) 80 (1) 88 (1) 58(1) −4 (1) 13 (1) −12 (1) O(1W)56 (1) 45 (1) 60(1) −7 (1) 7 (1) −2 (1) O(2W) 58 (1) 48 (1) 91(1) 3 (1)42 (1) 7 (1)

The anisotropic displacement exponent takes the form:

 −2π²(h ² a* ² U ₁₁+ . . . +2hka*b*U ₁₂)

TABLE VI H-Atom coordinates (×10⁴) and isotropic displacementcoefficients (Å² × 10³) x y z U H(2′) 6314 9385 6665 80 H(2A′) 8195 (10)8867 (10) 7105 (9) 50 H(3′) 5656 9704 5398 80 H(3A′) 8259 (10) 11720(10) 5037 (9) 50 H(4A′) 5234 (10) 6488 (10) 6270 (9) 50 H(2A) 2319 50611512 80 H(2B) 2495 6907 1046 80 H(2C) 1928 7053 1829 80 H(6A) 7999 46423381 80 H(6B) 6562 5972 3533 80 H(7A) 9771 (10) 7980 (10) 3431 (9) 50H(7B) 9183 (10) 7721 (10) 4160 (9) 50 H(8A) 7229 9605 3689 80 H(8B) 903310220 3630 80 H(9A) 8599 9685 2362 80 H(9B) 7101 10908 2520 80 H(10A)8417 4095 2071 80 H(10B) 9315 6067 2166 80 H(12) 9152 8192 1169 80 H(13)8559 8747 −149 80 H(14) 6799 6628 −864 80 H(15) 5710 4049 −375 80 H(16)6471 3406 915 80 H(1WA) 8471 (10) 5946 (10) 7323 (9) 52(1) H(1WB) 6863(10) 5969 (10) 7529 (9) 50 H(2WA) 11347 (10) 8095 (10) 5456 (9) 50H(2WB) 11515 (10) 9176 (10) 4829 (9) 50

Preparation One

Step A. 4-oxo-Piperidine-1,3-dicarboxylic Acid 1-tert-Butyl Ester3-Methyl Ester.

To a mixture of 7.00 g (36.2 mmol) of 4-oxo-piperidine-3-carboxylic acidmethyl ester and 8.82 g (72.3 mmol) of 4,4-dimethylaminopyridine in 200mL of methylene chloride at about 0° C. was added a solution of 7.88 g(36.2 mmol) of di-tert-butyldicarbonate in 150 mL of methylene chlorideover about 30 min. The mixture was warmed to room temperature and thenstirred for about 17 h. The mixture was concentrated and the residue wasdiluted with chloroform and washed three times each with 10% aqueousHCl, saturated aqueous sodium bicarbonate solution and brine, dried overMgSO₄ and concentrated to give 9.18 g of a clear yellow oil.

Step B. 3-(R,S)-Benzyl-4-oxo-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Methyl Ester.

To a solution of the compound prepared according to Step A (5.00 g, 19.4mmol) in 10 mL of DMF was added 745 mg (7.4 mmol) of sodium hydride (60%oil dispersion) and the mixture was stirred at room temperature forabout 15 min. A solution of 3.32 g (19.4 mmol) benzylbromide in 15 mL ofDMF was added to the stirring solution by cannula and the mixture wasstirred for about 42 h at room temperature. The mixture was diluted withethyl acetate and washed once with water and four times with brine,dried over MgSO₄, and concentrated to give 6.0 g of the title compoundof Step B as a yellow oil. MS (Cl, NH₃) 348 (MH⁺).

Step C.3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]-pyridine-5-carboxylicAcid tert-Butyl Ester.

A mixture of the compound prepared according to Step B (4.00 g, 11.5mmol) and 530 mg (11.5 mmol) of methylhydrazine in 100 mL of ethanol washeated at reflux for about 8 h. The mixture was concentrated and theresidue was dissolved in 100 mL toluene and heated at reflux for about17 h. The mixture was concentrated and the residue was purified bysilica gel chromatography using an elution gradient of (15:85 v/v ethylacetate:hexane) to (75:25 v/v ethyl acetate:hexane) to give 2.6 g of thetitle compound of Step C as a clear colorless oil. MS (Cl, NH₃) 344(MH⁺).

Step D.3a(R)-Benzyl-2-methyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(L)-Tartrate.

To a 2 liter, round bottom flask, equipped with a mechanical stirrer,addition funnel, and a thermocouple was added, sequentially,3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]-pyridine-5-carboxylicacid tert-butyl ester (prepared according to Step C, 51.5 g, 0.15 moles,1.0 equivalents) and methylene chloride (515 ml, 10 volumes). Themixture was agitated to form a solution which was then cooled to aninternal temperature of 0° C.-5° C. To the cooled mixture was addedtrifluoroacetic acid (TFA, 130 ml, 192 g, 1.68 moles, 11.2 eq., 2.5volumes). The TFA was added via the addition funnel over 15 minuteswhile maintaining an internal temperature of 0° C.-5° C. The reactionmixture was warmed to about 20° C. over 3 hours and then the reactionmixture was cooled to 10° C.-15° C. To the cooled reaction mixture wasadded sodium carbonate (92 g, 0.868 moles) in water (920 mL) over 20minutes. The pH was 7.5. The reaction mixture was transferred to a 2liter separatory funnel and allowed to settle. The organic portion wasdecanted and the aqueous portion was extracted with methylene chloride(130 ml, 2.5 volumes). The combined organic portions were transferredback to the 2 liter reactor and to it was added L-tartaric acid (24.77g, 0.165 moles, 1.1 equivalents) dissolved in acetone (354 ml, about 7volumes) and water (44 mL, about 1 volume). The reaction mixture wasagitated and heated at about 38° C. overnight. The resultant slurry wascooled to 0° C.-5° C., granulated for 1 hour, then filtered. The solidswere washed with 100 ml of cold acetone and then dried in vacuo at 40°C.-50° C. for 16 hours to afford 51.86 g (87.9% yield) of the titlecompound of Step D.

Preparation Two

Step A 4-oxo-3-Pyridin-2-yl-methyl-piperidine-1,3-dicarboxylic Acid1-tert-Butyl Ester 3-Ethyl Ester.

To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-ethyl ester (prepared according to the method of PreparationOne, Step A, 10.34 g, 38.2 mmol) in DMF (40 mL) at about 0° C. was addedpicolyl chloride hydrochloride (5.7 g, 34.7 mmol), potassium carbonate(14.4 g, 104.1 mmol) and potassium iodide (5.76 g, 34.7 mmol). Afterstirring at about 0° C. for about 2 hours, the ice bath was removed andDABCO (973 mg, 8.68 mmol) was added. The reaction mixture was stirredfor about 30 min. and poured into a mixture of water and IPE. Theorganic layer was separated and washed with saturated aqueous NaHCO₃ andsaturated aqueous NaCl, dried over Na₂SO₄ and concentrated in vacuo. Thecrude residue was crystallized from hexanes to give a white solid (8.19g, yield 65%). ¹H-NMR (CDCl₃) δ 1.17 (t, 3H), 1.48 (s, 9H), 1.55 (s,2H), 2.61 (m, 1H), 2.71 (m, 1H), 3.31-3.50 (m, 3H), 4.11 (d, 2H), 4.49(d, 1H), 7.06 (br, s, 1H), 7.17 (d, 1H), 7.54 (m, 1H), 8.40 (s, 1H).

Step B.3-oxo-3a-Pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicAcid tert-Butyl Ester.

A 70% aqueous solution of CF₃CH₂NHNH₂ (325 mL, 1.986 mol) was extractedwith toluene (3×1200 mL). To a solution of the compound preparedaccording to step A (600 g, 1.655 mol) in toluene (900 mL) was firstadded the combined toluene extracts containing the anhydrous2,2,2-trifluoroethyl hydrazine, followed by acetic acid (121.4 g, 1.986mol). The reaction mixture was heated at about 70° C. for about 2 hours,then another toluene extraction of 70% aqueous 2,2,2-trifluoroethylhydrazine (50 g) was added. The reaction mixture was heated at about 80°C. for about 3.5 hours, cooled to room temperature and diluted withsaturated aqueous NaHCO₃ (2 L). The toluene layer was separated andwashed with saturated aqueous NaCl, dried over Na₂SO₄ and concentratedin vacuo to give an oil (754.8 g). Crystallization from methanol/waterafforded the desired product as a white solid (609.5 g). ¹H-NMR (CDCl₃)δ 1.50 (s, 9H), 2.53 (d, 1H), 2.70 (br, s, 2H), 2.88 (br, s, 1H), 3.31(m, 2H), 3.97 (m, 1H), 4.19 (m, 1H), 4.46 (br, s, 1H), 4.63 (br, s, 1H),7.06 (m, 2H), 7.51(m, 1H), 8.34 (m, 1H).

Step C.3a-Pyridin-2-yl-methyl-2-(2,2,2-trifluoroethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one.

Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to a solutionof the compound prepared according to step B (10 g, 24.2 mmol) in CH₂Cl₂(100 mL) over about 30 minutes. The reaction mixture was stirred forabout 1 hour, then cooled to about 0° C., and then triethylamine (18.6mL, 133.1 mmol) was added through an addition funnel. The mixture wasallowed to warm to room temperature over about 1 hour, diluted withadditional CH₂Cl₂ and washed with saturated aqueous NaCl, dried overNa₂SO₄, filtered and concentrated in vacuo to afford the product as awhite solid (7.2 g). ¹H-NMR (CDCl₃) δ: 2.51-2.72 (m, 4H), 3.35 (m, 2H),3.49 (m, 2H), 4.03 (m, 1H), 4.25 (m, 1H), 7.08 (d, 2H), 7.51 (t, 1H),8.37 (d, 1H).

Step D.3a-Pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one(D)-Tartrate.

In a dry and nitrogen purged 5 L round bottom flask equipped with amechanical stirrer, D-(−) tartaric acid (129 g, 0.86 mol) was added tothe compound prepared according to step C (243 g, 0.78 mol) inacetone/water (9:1, 2430 mL) at about 17° C. The mixture was stirred atroom temperature overnight, filtered, the solid was collected and washedwith cold acetone and dried under vacuum. The product was obtained as ayellow solid (284 g, yield 78.8%).

Preparation Three

Step A. 2-tert-Butoxycarbonylamino-2-methyl-propionic Acid2,5-Dioxo-pyrrolidin-1-yl Ester.

A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol),N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) inanhydrous dichloromethane (1.4 L) was stirred at room temperature forabout 18 hours under nitrogen atmosphere. The reaction mixture waswashed three times each with saturated sodium bicarbonate solution andthen brine. The organic layer was dried over sodium sulfate, filteredand concentrated in vacuo to give the title compound of Step A as awhite solid (256 g, 88%): PBMS (M+18)⁺318; ¹H NMR=250 MHz (CDCl₃) δ:4.91 (NH, br, s, 1H), 2.84 (—CO(CH ₂)₂CO—, s, 4H), 1.67 (Me, s, 6H),1.48 (BOC, s, 9H).

Step B.2(R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicAcid.

To a solution of D-O-benzylserine (106 g, 0.532 mol) and the titlecompound of Step A (160 g, 0.532 mol) in water/dioxane (250/1000 mL) wasslowly added triethylamine (223 mL, 1.60 mol) at room temperature. Thereaction was heated to about 50° C. and stirred for about 15 hours undernitrogen atmosphere. The solvent was then removed in vacuo, ethylacetate was added, and the stirred mixture was acidified with 10%aqueous HCl solution to pH 2-3. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to give the title compoundof Step B (200 g, 99%): -Apcl MS (M−1)⁻ 379; ¹H NMR=300 MHz(methanol-d₄) δ :7.69 (NH, d, 1H), 7.32 (Ph, m, 5H), 4.60 (CHCO₂H, m,1H), 4.51 (CH ₂Ph, s, 2H), 3.81 (CH ₂Obz, m, 2H), 1.41 (Me, s, 6H), 1.40(BOC, s, 9H).

Preparation Four

Step A2(R)-2-tert-Butoxycarbonylamino-3-(2,4-difluoro-benzyloxy)-propionicAcid.

To a solution of N-Boc-(D)-serine (452 g, 2.2026 mol) in a mixture ofTHF (7 L) and DMF (3 L) at about 0° C. was added potassium tert-butoxidesolution (515.8 g, 4.5963 mol). The reaction mixture was stirred atabout 0° C. for about 30 min., then 2,4-difluorobenzyl bromide (456.5 g,2.2051 mol) was added. After warming to room temperature, the reactionmixture was concentrated in vacuo to remove the THF. The reactionmixture was partitioned between 4.5 L H₂O and 4.5 L IPE. The layers wereseparated and the pH of the aqueous layer was adjusted with 1 N HCl toabout 3. The aqueous layer was extracted twice with 4 L each of IPE. Theorganic solution was dried over Na₂SO₄, and concentrated in vacuo toyield a yellow waxy solid (518.0 g, yield: 70.9%). ¹H-NMR (CDCl₃) δ 1.44(s, 9H), 3.73 (m, 1H), 3.94 (d, 1H), 4.44 (br, s, 1H), 4.54 (s, 2H),5.34 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 7.30 (m, 1H).

Step B. 2(R)-2-Amino-3-(2,4-difluoro-benzyloxy)-propionic Acid,Methanesulfonic Acid Salt.

To a solution of the product from Step A (1.19 g, 3.59 mmol) inCH₂Cl₂/IPE (1:1, 12 mL) was added methanesulfonic acid (1.72 g, 17.95mmol) through a syringe over about 10 minutes. A solid immediatelyprecipitated out of solution. After about 1 hour, the solid was filteredand washed with a CH₂Cl₂/IPE mixture (1:1) to afford 939 mg of product(yield 80%).

Step C.2(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(2,4-difluoro-benzyloxy)-propionicAcid.

To a solution of the product from Step B (520 mg, 1.46 mmol) inTHF/water (4:1, 10 mL) was added2-tert-butoxycarbonylamino-2-methyl-propionicacid-2,5-dioxo-pyrrolidin-1-yl ester (438 mg, 1.46 mmol) andtriethylamine (369 mg, 3.65 mmol). The reaction mixture was stirred atroom temperature for about 1 hour and quenched with a 10% aqueous citricacid solution (10 mL). After about 15 min., ethyl acetate (50 mL) wasadded and the organic layer was separated and washed with saturatedaqueous NaCl, dried over Na₂SO₄ and concentrated in vacuo to give a foam(534.1 mg, yield 88%). ¹H-NMR (CD₃OD): 61.38 (br, s, 15H), 3.77 (d, 1H),3.92 (d, 1H), 4.52 (m, 3H), 6.92 (m, 1H), 7.41 (m, 1H), 7.58 (d, 1H).

Preparation Five(3aR)-2,3a,4,5,6,7-Hexahydro-2-methyl-3a-(Phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one,(2R,3R)-2,3-Dihydroxybutanedioate (1:1)

Step A: 4-oxo-1-(Phenylmethyl)-3-piperidinecarboxylic Acid Methyl Ester,Hydrochloride.

A solution of 1-benzyl4-piperidone (56.5 kg, 1.0 eq.) in toluene (189 L)was prepared at 15° C. to 25° C. A second reactor was charged withtoluene (659 L), potassium tert-butoxide (71.9 kg, 2.25 eq.) anddimethyl carbonate (51.5 kg, 2.0 eq.) at 15° C. to 25° C. The resultingslurry was warmed to a temperature of 80° C. to 90° C. The solution of1-benzyl-4-piperidone in toluene was added slowly to the slurry over 60to 90 minutes. After an additional 90 minutes, the reaction mixture wascooled to below 15° C. The completed reaction was quenched with aceticacid (38.5 kg, 2.25 eq.) and water (367 L). The two phase mixture wasseparated. The organic layer was filtered to remove solids. The organicfiltrate was concentrated by distillation under reduced pressure to avolume of approximately 150 L. Toluene (799 L) was added to theconcentrated mixture. Addition of hydrogen chloride (gas, 11.0 kg, 1.05eq.) afforded the hydrochloride salt as a precipitate. The slurry wasstirred at 10° C. to 15° C. for 30 minutes. The solids were isolated byfiltration, washed with approximately hexanes (130 L), and dried usingvacuum to give 79.4 kg of 4-oxo-1-(phenylmethyl)-3-piperidinecarboxylicacid methyl ester, hydrochloride (97.8% yield). Analysis calculated forC₁₄H₁₇NO₃.HCl: C 59.3; H 6.39; N 4.94; found: C 59.7H, 6.65 N, 4.85.

Step B: 4-oxo-1-Piperidinecarboxylic Acid Methyl ester, Hydrochloride.

Into a clean, dry, nitrogen purged reactor was added4-oxo-1-(phenylmethyl)-3-piperidinecarboxylic acid methyl ester,hydrochloride (prepared according to Preparation Five, Step A, 78.8 kg,1.0 eq.), ethanol (416 L), water (340 L), and 10% palladium on carbon(catalyst, 7.88 kg, 0.1 kg/kg). The mixture was subjected tohydrogenation conditions of approximately 45 psig (32×10³ kg/m²) ofhydrogen pressure at a temperature between 25° C. to 35° C. forapproximately 18 hours. After the reaction was complete, the reactionmixture was vented with nitrogen and filtered to removed the spentcatalyst. The catalyst cake was washed with ethanol (150 L). Thefiltrate and washes were concentrated under reduced pressure toapproximately 57 L. The product was crystallized by the slow addition of2-propanol (227 L). The slurry was cooled to 10° C. to 20° C. andstirred for approximately one hour. The product was isolated byfiltration, rinsed with hexanes (76 L), and dried under vacuum forapproximately 24 hours to give 43.2 kg 4-oxo-1-piperidinecarboxylic acidmethyl ester, hydrochloride (80.0% yield). Analysis calculated forC₇H₁₁NO₃.HCl: C 43.42; H 6.25; N 7.23; found: C 43.7; H 6.59; N 7.19.

Step C: 4-oxo-1,3-Piperidinecarboxylic Acid 1-(1,1-Dimethylethyl)3-Methyl Ester.

A clean, dry, nitrogen purged, glass-lined vessel was charged withisopropyl ether (IPE, 309 L), 4-oxo-1-piperidinecarboxylic acid methylester, hydrochloride (prepared according to Preparation Five, Step B,42.6 kg, 1.0 eq.), and water (153 L) at 15 to 25° C. Addition oftriethylamine (28.9 kg, 1.3 eq.) resulted in a thick white emulsion.Slow addition of di-tert-butyldicarbonate (52.6 Kg, 50 L, 1.1 eq.) tothe reaction mixture, followed by an IPE rinse, resulted in a clearbiphasic solution. The mixture was agitated at 15° C. to 25° C. forabout 12 hours. After reaction completion, the aqueous layer wasseparated off and extracted with IPE (20 L). The organic extracts werecombined and washed sequentially with 1N HCl (110 L), water (90 L), andsaturated sodium chloride solution (103 L). The washed organic layer wasdried over anhydrous sodium sulfate. The mixture was filtered to removeinsolubles. The filtrate was concentrated using vacuum distillation togive the oil 4-oxo-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl)3-methyl ester. About 49 L (53 kg) of product oil (assumed 95% yield)was collected. The oil was held in the reactor for immediate use in thenext step.

Step D: 4-oxo-3-(Phenylmethyl)-1,3-piperidinedicarboxylic Acid1-(1,1-Dimethylethyl) 3-Methyl Ester.

The nitrogen purged vessel containing about4-oxo-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methylester (prepared according to Preparation Five, Step C, 53 kg, 49 L, 1.0eq.) was charged with tetrahydrofuran (THF, 536 L) and potassiumcarbonate (72 kg, 2.5 eq.). The slurry was treated with benzyl bromide(36.0 kg, 1.01 eq.) over 10 to 15 minutes. The reaction mixture washeated at reflux temperature until reaction was complete (generallybetween 12 and 18 hours). The mixture was cooled to between 20° C. and25° C., filtered to remove the salts, and the filter cake washed withTHF (134 L). The THF was removed from the mixture by partial vacuumdistillation and replaced with heptanes (402 L). The resulting slurrywas cooled to between −5° C. and 5° C. and stirred for about one hour.The solids were collected by filtration, washed with heptanes (57 L)cooled between 0° C. to 10° C., and dried under vacuum between 45° C. to55° C. to give 50.1 kg of4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid1-(1,1-dimethylethyl) 3-methyl ester (69.2% yield). HPLC assay showed aproduct peak of 99.2% at about 12 minutes. HPLC conditions: Intersil C-8column, 4.6×150 mm; mobile phase: 50%acetonitrile/water; aqueous phase:1 L water, 3 mL triethylamine and 1 mL H₃PO₄ at pH 6.5; flow rate 1.0mL/min.; detected by UV at 210 nm.

Step E:2,3,3a,4,6,7-Hexahydro-2-methyl-3-oxo-3a-(Dhenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylicAcid 1,1-Dimethylethyl Ester.

Methylhydrazine is highly toxic, is a cancer suspect agent, is flammableand is potentially explosive. It should be handled with extreme care.Have spill kits, drying agents, liqua paks and fire extinguishers onhand during handling. Ensure air hoses are long enough to escape anyaccident scene. Since methylhydrazine can react with metal oxides, thereaction vessel was inspected to ensure that no metal surfaces wereexposed prior to initiating the reaction. In a clean, glass-lined,nitrogen purged vessel,4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid1-(1,1-dimethylethyl) 3-methyl ester (prepared according to PreparationFive, Step D, 50.1 kg, 1.0 eq.) was dissolved in methyl-t-butyl ether(MTBE, 208 L) at 15° C. to 20° C. to form a solution. The reactionsolution was charged with methylhydrazine (7.6 kg, 1.15 eq.). Afterstirring for about 30 minutes, acetic acid (13.0 kg, 1.5 eq.) was added.The reaction mixture was slowly heated to reflux temperature (53° C. to57° C.) and held at reflux for 15 to 20 hours. The reaction was cooledto between 20° C. and 25° C. The reaction mixture was cooled to between5° C. and 10° C. and slowly charged with 10% sodium bicarbonate solutionin water (175 L). The biphasic mixture was separated and the organiclayer was washed sequentially with water (175 L) and saturated sodiumchloride solution (175 L). The aqueous wash layers should be combinedand treated with bleach solution to destroy any residual methylhydrazineprior to disposal. The organic solution was concentrated to a volumebetween 130 and 170 L under partial vacuum. Addition of heptanes (174 L)to the mixture precipitated the product. The slurry was stirred for 2hours at a temperature between 5° C. and 10C. The solids were isolatedby filtration, washed with cold MTBE (34 L), and dried under vacuum at atemperature between 35° C. and 45° C. for 24 hours to give 47.1 kg of2,3,3a,4,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylicacid 1,1-dimethylethyl ester (95.1% yield). HPLC assay showed a productpeak of 99.1% at about 5 minutes. HPLC conditions: Intersil C-8 column,4.6×150 mm; mobile phase: 50%acetonitrile/water; aqueous phase: 1 Lwater, 3 mL triethylamine and 1 mL H₃PO₄ at pH 6.5; flow rate 1.0mL/min.; detected by UV at 205 nm.

Step F:(3aR)-2,3a,4,5,6,7-Hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one,(2R,3R)-2,3-Dihydroxybutanedioate (1:1).

It has been observed that the intermediate free amine epimerizes insolution and as an isolated solid. Therefore, the dynamic resolutionstep was completed immediately following the deprotection step. A clean,nitrogen purged reactor was charged with methylene chloride (471 L) and2,3,3a,4,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylicacid 1,1-dimethylethyl ester (prepared according to Preparation Five,Step E, 47.0 kg, 1.0 eq.). The mixture was agitated and cooled tobetween −5° C. and 5° C. The reaction mixture was slowly charged withtriflouroacetic acid (117 kg, 7.5 eq.). The reaction mixture was warmedto a temperature between 20° C. and 30° C. and stirred for 12 to 15hours. The reaction mixture was quenched by slow addition of an aqueoussolution of 10% sodium carbonate (486 L, 0.5 eq.) at a temperaturebetween 5° C. and 15° C. The organic layer was separated and the aqueouslayer extracted with methylene chloride (19 L).

A mixture of acetone (456 L), water (56.4 L), and L-tartaric acid (22.6kg, 1.1 eq.) was prepared in a second reactor. The tartaric acid mixturewas combined with the organic layers at a temperature between 20° C. and25° C. The resulting slurry was heated to a temperature between 35° C.and 45° C. and stirred for 8 to 18 hours (overnight). When the reactionwas judged to be complete, the slurry was cooled and granulated at atemperature between 0° C. and 10° C. for three to four hours andfiltered. The product cake was washed with a mixture of acetone (40 L)and water (4.5 L). The product was dried under vacuum using only mildheat (applied if evaporation of acetone results in cooling). A yield of37.7 kg of(3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one,(2R,3R)-2,3-dihydroxybutanedioate (1:1) was obtained (70.1% yield).

What is claimed is:
 1. A process of preparing a compound of Formula II,

wherein: R¹ is —(C₁-C₁₀)alkyl optionally substituted with up to threefluoro atoms; R² is phenylmethyl or 2-pyridylmethyl; R³ is—(C₁-C₅)alkyl-O—(C₀-C₅)alkylphenyl, where the phenyl substituent in thedefinition of R³ is optionally substituted with up to three fluoroatoms; and Prt is an amine protecting group, comprising: a) mixing anappropriate chiral tartrate salt having the structure of Formula IV,

wherein R¹ and R² are as defined above, and an organic amine in areaction inert solvent at a temperature of about −68° C. to about −40°C. to form a slurry; b) adding a compound of the Formula V,

wherein R³ and Prt are as defined above, to said slurry to form areaction mixture comprising the tartrate salt of the organic amine, thefree base of a compound of Formula IV and a compound of the formula V;and c) adding a coupling reagent to said reaction mixture to form acompound of Formula II.
 2. A process of claim 1 wherein said compound ofFormula IV is suspended in said solvent prior to the addition of saidorganic amine.
 3. A process of claim 2 wherein said slurry is warmed toabout −50° C. prior to step b.
 4. A process of claim 1 wherein: in stepa, said organic amine is triethylamine; in step b, R³ isphenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt istert-butyloxycarbonyl; and in step c, said coupling reagent is propanephosphonic acid anhydride.
 5. A process of claim 4 wherein R¹ is methylor 2,2,2-trifluoroethyl and R² is phenylmethyl or 2-pyridylmethyl.
 6. Aprocess of claim 5 wherein the compound of Formula II selected from(1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester and(1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester is prepared.
 7. A process of claim 5 wherein acompound of Formula IIA,

wherein Boc is tert-butloxycarbonyl, is prepared.
 8. A process of claim5 wherein a compound of Formula IIB,

wherein Boc is tert-butyloxycarbonyl, is prepared.
 9. A process of claim2 wherein: in step a, said organic amine is triethylamine; in step b, R³is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt istert-butyloxycarbonyl; and in step c, said coupling reagent is propanephosphonic acid anhydride.
 10. A process of claim 9 wherein R¹ is methylor 2,2,2-trifluoroethyl and R² is phenylmethyl or 2-pyridylmethyl.
 11. Aprocess of claim 10 wherein the compound of Formula II selected from(1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester and(1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester is prepared.
 12. A process of claim 10 wherein acompound of Formula IIA,

wherein Boc is tert-butyloxycarbonyl, is prepared.
 13. A process ofclaim 10 wherein a compound of Formula IIB,

wherein Boc is tert-butyloxycarbonyl, is prepared.
 14. A process ofclaim 3 wherein: in step a, said organic amine is triethylamine; in stepb, R³ is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl andPrt is tert-butyloxycarbonyl; and in step c, said coupling reagent ispropane phosphonic acid anhydride.
 15. A process of claim 14 wherein R¹is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.
 16. A process of claim 15 wherein the compound ofFormula II selected from(1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester and(1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamicacid tert-butyl ester is prepared.
 17. A process of claim 15 wherein acompound of Formula IIA,

wherein Boc is tert-butyloxycarbonyl is prepared.
 18. A process of claim15 wherein a compound of Formula IIB,

wherein Boc is tert-butyloxycarbonyl is prepared.
 19. A process forpreparing a compound of Formula III,

wherein: R¹ is —(C₁-C₁₀)alkyl optionally substituted with up to threefluoro atoms; R² is phenylmethyl or 2-pyridylmethyl; and R³ is—(C₁-C₅)alkyl-O—(C₀-C₅)alkylphenyl, where the phenyl substituent in thedefinition of R³ is optionally substituted with up to three fluoroatoms, comprising: a) mixing an appropriate chiral tartrate salt havingthe structure of Formula IV,

wherein R¹ and R² are as defined above, and an organic amine in areaction inert solvent at a temperature of about −68° C. to about −45°C. to form a slurry; b) adding a compound of the Formula V,

wherein R³ is as defined above and Prt is an amine protecting group, tosaid slurry to form a reaction mixture comprising the tartrate salt ofthe organic amine, the free base of a compound of Formula IV and acompound of the Formula V; c) adding a coupling reagent to said reactionmixture to form a compound of Formula II; and d) reacting said compoundof Formula II with a suitable deprotecting reagent to form a compound ofFormula III.
 20. A process of claim 19 wherein said compound of FormulaIV is suspended in said solvent prior to the addition of said organicamine comprising the additional step of warming said slurry to about−50° C. to about −40° C. prior to step b.
 21. A process of claim 20wherein said Prt is tert-butyloxycarbonyl and said tert-butyloxycarbonylis removed by reacting said compound of Formula II with an acid.
 22. Aprocess of claim 21 wherein said acid is methanesulfonic acid.
 23. Aprocess of claim 22 wherein: R³ is phenylmethyloxymethyl or2,4-difluorophenylmethyloxymethyl; in step b, said organic amine istriethylamine; and in step c, said coupling reagent is propanephosphonic acid anhydride.
 24. A process of claim 23 wherein R¹ ismethyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.
 25. A process of claim 24 wherein said compound ofFormula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamideis prepared.
 26. A process of claim 24 wherein a compound of formulaIIIA,

is prepared.
 27. A process of claim 24 wherein a compound of formulaIIIB,

is prepared.
 28. A process of claim 21 wherein said acid istrifluoroacetic acid.
 29. A process of claim 28 wherein: R³ isphenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b,said organic amine is triethylamine; and in step c, said couplingreagent is propane phosphonic acid anhydride.
 30. A process of claim 29wherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.
 31. A process of claim 30 wherein said compound ofFormula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamideis prepared.
 32. A process of claim 30 wherein a compound of formulaIIIA,

is prepared.
 33. A process of claim 30 wherein a compound of formulaIIIB,

is prepared.
 34. A process of claim 19 wherein said Prt istert-butyloxycarbonyl and said tert-butyloxycarbonyl is removed byreacting said compound of Formula II with an acid.
 35. A process ofclaim 34 wherein said acid is methanesulfonic acid.
 36. A process ofclaim 35 wherein: R³ is phenylmethyloxymethyl or2,4-difluorophenylmethyloxymethyl; in step b, said organic amine istriethylamine; and in step f, said coupling reagent is propanephosphonic acid anhydride.
 37. A process of claim 36 wherein R¹ ismethyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.
 38. A process of claim 37 wherein said compound ofFormula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide.39. A process of claim 37 wherein a compound of formula IIIA,

is prepared.
 40. A process of claim 37 wherein a compound of formulaIIIB,

is prepared.
 41. A process of claim 34 wherein said acid istrifluoroacetic acid.
 42. A process of claim 41 wherein: R³ isphenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b,said organic amine is triethylamine; and in step f, said couplingreagent is propane phosphonic acid anhydride.
 43. A process of claim 42wherein R¹ is methyl or 2,2,2-trifluoroethyl and R² is phenylmethyl or2-pyridylmethyl.
 44. A process of claim 43 wherein said compound ofFormula III selected from2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramideand2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide.45. A process of claim 43 wherein a compound of formula IIIA,

is prepared.
 46. A process of claim 43 wherein a compound of formulaIIIB,

is prepared.
 47. A polymorph of a dihydrate of a compound of formula XX:


48. A polymorph of claim 47 having the X-Ray crystal structure accordingto FIG.
 1. 49. A polymorph of claim 47 having the atomic coordinates andequivalent isotropic displacement coefficients as set forth in Table II:TABLE II Atomic coordinates (×10⁴) and equivalent isotropic displacementcoefficients (Å² × 10³) x y z U(eq) C(1′) 7050 (7) 12045 (7) 6424 (4)31(1) O(1A′) 5715 (5) 12748 (6) 6097 (3) 41(1) O(1B′) 8234 (5) 12946 (6)6748 (3) 41(1) C(2′) 7120 (6) 9881 (7) 6388 (4) 29(1) O(2′) 8733 (5)9232 (6) 6715 (3) 37(1) C(3′) 6707 (7) 9167 (7) 5599 (4) 32(1) O(3′)7899 (5) 9726 (6) 5160 (3) 47(1) C(4′) 6647 (7) 6999 (7) 5583 (4) 32(1)O(4A′) 5644 (5) 6263 (6) 5971 (3) 39(1) O(4B′) 7465 (5) 6110 (7) 5213(3) 59(1) N(1) 5011 (6) 8379 1995 (3) 43(1) N(2) 4317 (6) 6558 (7) 1896(3) 40(1) C(2A) 2623 (6) 6380 (8) 1541 (4) 55(1) C(3) 5357 (7) 5149 (8)2171 (4) 36(1) O(3) 5039 (5) 3491 (6) 2188 (3) 46(1) C(4) 6998 (6) 6172(8) 2450 (3) 28(1) C(5) 6515 (6) 8177 (8) 2299 (4) 33(1) C(6) 7511 (6)5878 (8) 3290 (4) 39(1) N(7) 8723 (6) 7355 (7) 3591 (3) 40(1) C(8) 8153(7) 9366 (8) 3440 (4) 49(1) C(9) 7643 (7) 9700 (8) 2603 (4) 46(1) C(10)8290 (6) 5440 (8) 1989 (4) 37(1) C(11) 7862 (7) 5776 (8) 11667 (4) 43(1)C(12) 8463 (7) 7317 (8) 853 (4) 69(1) C(13) 8108 (8) 7675 (9) 76 (5)97(1) C(14) 7080 (*) 6405 (9) −336 (5) 96(1) C(15) 6443 (8) 4882 (8) −59(5) 81(1) C(16) 6872 (7) 4533 (8) 705 (4) 75(1) O(1W) 8100 (5) 6278 (7)7609 (3) 54(1) O(2W) 10828 (5) 8138 (7) 5099 (3) 62(1)


50. A polymorph of claim 49 further having the bond lengths as set forthin Table III: TABLE III Bond Lengths (Å) C(1′)-O(1A′) 1.262(7)C(1′)-O(1B′) 1.229 (7) (C1′)-C(2′) 1.525(7) C(2′)-O(2′) 1.4347 (6)C(2′)-C(3′) 1.500(9) C(3′)-O(3′) 1.416 (8) C(3′)-C(4′) 1.526(7)C(4′)-O(4A′) 1.277 (8) C(4′)-O(4B′) 1.201(8) N(1)-N(2) 1.402 (5)N(1)-C(5) 1.278(7) N(2)-C(2A) 1.443 (7) N(2)-C(3) 1.350(7) C(3)-O(3)1.196 (7) C(3)-C(4) 1.541(7) C(4)-C(5) 1.478 (7) C(4)-C(6) 1.526(9)C(4)-C(10) 1.544 (9) C(5)-C(9) 1.465(7) C(6)-N(7) 1.481 (7) N(7)-C(8)1.501(7) C(8)-C(9) 1.524 (10) C(10)-C(11) 1.492(9) C(11)-C(12) 1.355 (9)C(11)-C(16) 1.380(8) C(12)-C(13) 1.411 (12) C(13)-C(14) 1.365(9)C(14)-C(15) 1.327 (10) C(15)-C(16) 1.393(11)


51. A polymorph of claim 50 further having the bond angles as set forthin Table IV: TABLE IV Bond Angles (°) O(1A′)-C(1′)-O(1B′) 125.8(5)O(1A′)-C(1′)-C(2′) 114.1(5) O(1B′)-C(1′)-C(2′) 120.2(5)C(1′)-C(2′)-O(2′) 109.8(4) C(1′)-C(2′)-C(3′) 111.7(5) O(2′)-C(2′)-C(3′)109.7(5) C(2′)-C(3′)-O(3′) 111.9(4) C(2′)-C(3′)-C(4′) 110.7(5)O(3′)-C(3′)-C(4′) 106.9(5) C(3′)-C(4′)-O(4A′) 114.6(5)C(3′)-C(4′)-O(4B′) 120.7(6) O(4A′)-C(4′)-O(4B′) 124.6(5) N(2)-N(1)-C(5)107.4(3) N(1)-N(2)-C(2A) 118.7(4) N(1)-N(2)-C(3) 113.8(4)C(2A)-N(2)-C(3) 127.5(5) N(2)-C(3)-O(3) 126.6(5) N(2)-C(3)-C(4) 104.3(4)O(3)-C(3)-C(4) 129.0(5) C(3)-C(4)-C(5) 100.9(4) C(3)-C(4)-C(6) 110.4(5)C(5)-C(4)-C(6) 109.6(5) C(3)-C(4)-C(10) 108.2(5) C(5)-C(4)-C(10)114.0(5) C(6)-C(4)-C(10) 113.0(4) N(1)-C(5)-C(4) 113.4(4) N(1)-C(5)-C(9)126.2(4) C(4)-C(5)-C(9) 119.5(4) C(4)-C(6)-N(7) 109.4(5) C(6)-N(7)-C(8)115.0(4) N(7)-C(8)-C(9) 110.7(5) C(5)-C(9)-C(8) 108.4(5)C(4)-C(10)-C(11) 114.5(4) C(10)-C(11)-C(12) 120.2(5) C(10)-C(11)-C(16)121.6(6) C(12)-C(11)-C(16) 118.3(7) C(11)-C(12)-C(13) 122.0(6)C(12)-C(13)-C(14) 115.9(7) C(13)-C(14)-C(15) 124.7(8) C(14)-C(15)-C(16)117.8(6) C(11)-C(16)-C(15) 121.2(6)


52. A polymorph of claim 51 further having the anisotropic displacementcoefficients as set forth in Table V: TABLE V Anisotropic displacementcoefficients (Å² × 10³) U₁₁ U₂₂ U₃₃ U₁₂ U₁₃ U₂₃ C(1′) 32 (1) 26 (1)34(1) 2 (1) 5 (1) −8 (1) O(1A′) 35 (1) 19 (1) 67(1) −4 (1) 2 (1) 2 (1)O(1B′) 35 (1) 26 (1) 60(1) −4 (1) −2 (1) −13 (1) C(2′) 32 (1) 17 (1)36(1) 1 (1) −1 (1) 1 (1) O(2′) 32 (1) 33 (1) 43(1) 4 (1) −1 (1) 0 (1)C(3′) 41 (1) 18 (1) 37(1) 6 (1) 6 (1) −6 (1) O(3′) 71 (1) 33 (1) 41(1)−2 (1) 23 (1) 1 (1) C(4′) 28 (1) 27 (1) 39(1) 2 (1) 3 (1) 2 (1) O(4A′)41 (1) 32 (1) 45(1) −7 (1) 10 (1) −9 (1) O(4B′) 56 (1) 35 (1) 92(1) 7(1) 32 (1) −2 (1) N(1) 39 (1) 48 (1) 37(1) 4 (1) −6 (1) 7 (1) N(2) 30(1) 39 (1) 47(1) 2 (1) −2 (1) −4 (1) C(2A) 27 (1) 66 (1) 68(1) −3 (1) −2(1) −1 (1) C(3) 39 (1) 40 (1) 30(1) 8 (1) 10 (1) −7 (1) O(3) 45 (1) 27(1) 65(1) −3 (1) 5 (1) 1 (1) C(4) 23 (1) 34 (1) 26(1) 0 (1) 2 (1) 3 (1)C(5) 31 (1) 32 (1) 36(1) −1 (1) 6 (1) 0 (1) C(6) 38 (1) 38 (1) 38(1) 4(1) 1 (1) −4 (1) N(7) 39 (1) 42 (1) 34(1) 1 (1) −6 (1) −1 (1) C(8) 44(1) 46 (1) 54(1) −1 (1) 1 (1) −9 (1) C(9) 41 (1) 42 (1) 52(1) 6 (1) 2(1) 0 (1) C(10) 37 (1) 46 (1) 29(1) 6 (1) 9 (1) 4 (1) C(11) 39 (1) 55(1) 37(1) 10 (1) 7 (1) −2 (1) C(12) 72 (1) 85 (1) 49(1) 4 (1) 2 (1) 1(1) C(13) 103 (1) 108 (1) 82(1) 2 (1) 16 (1) 27 (1) C(14) 103 (1) 108(1) 73(1) 13 (1) 4 (1) 6 (1) C(15) 81 (1) 93 (1) 63(1) −4 (1) −6 (1) −17(1) C(16) 80 (1) 88 (1) 58(1) −4 (1) 13 (1) −12 (1) O(1W) 56 (1) 45 (1)60(1) −7 (1) 7 (1) −2 (1) O(2W) 58 (1) 48 (1) 91(1) 3 (1) 42 (1) 7 (1)


53. A polymorph of claim 52 further having the hydrogen atom coordinatesand isotropic displacement coefficients as set forth in Table VI: TABLEVI H-Atom coordinates (×10⁴) and isotropic displacement coefficients (Å²× 10³) x y z U H(2′) 6314 9385 6665 80 H(2A′) 8195 (10) 8867 (10) 7105(9) 50 H(3′) 5656 9704 5398 80 H(3A′) 8259 (10) 11720 (10) 5037 (9) 50H(4A′) 5234 (10) 6488 (10) 6270 (9) 50 H(2A) 2319 5061 1512 80 H(2B)2495 6907 1046 80 H(2C) 1928 7053 1829 80 H(6A) 7999 4642 3381 80 H(6B)6562 5972 3533 80 H(7A) 9771 (10) 7980 (10) 3431 (9) 50 H(7B) 9183 (10)7721 (10) 4160 (9) 50 H(8A) 7229 9605 3689 80 H(8B) 9033 10220 3630 80H(9A) 8599 9685 2362 80 H(9B) 7101 10908 2520 80 H(10A) 8417 4095 207180 H(10B) 9315 6067 2166 80 H(12) 9152 8192 1169 80 H(13) 8559 8747 −14980 H(14) 6799 6628 −864 80 H(15) 5710 4049 −375 80 H(16) 6471 3406 91580 H(1WA) 8471 (10) 5946 (10) 7323 (9) 52(1) H(1WB) 6863 (10) 5969 (10)7529 (9) 50 H(2WA) 11347 (10) 8095 (10) 5456 (9) 50 H(2WB) 11515 (10)9176 (10) 4829 (9) 50